MEPE/OF45在DNA损伤应答中的作用研究
摘要
细胞外基质磷酸糖蛋白/成骨细胞/骨细胞因子45 (Matrix Extracellular PhosphoglycoprotEin/Osteoblast/Osteocyte Factor 45, MEPE/OF45)自2000年被首次克隆以来,作为小型的N-端连接整合素的糖蛋白(Small Integrin -Binding Ligand, N-linked Glycoprotein, SIBLING)家族的一员,它的功能研究就一直局限在调节骨代谢和磷(体内)平衡方面。我们的前期研究揭示了MEPE/OF45蛋白的新功能,即MEPE/OF45参与细胞DNA损伤应答;MEPE/OF45能够增强细胞对DNA损伤诱导剂(DNA Damage Inducers)的耐受性,这种功能的发挥是通过MEPE/OF45蛋白与检验点激酶1 (Checkpoint Kinase 1, CHK1 )之间的相互作用而实现的;MEPE/OF45能够通过与泛素E3连接酶竞争性结合CHK1而抑制其泛素化降解。美国王亚教授实验室检测到MEPE/OF45在人中的同源蛋白人MEPE/OF45在各种组织来源的肿瘤细胞中均有表达,而且表达水平与肿瘤细胞对DNA损伤诱导剂(包括电离辐射、抗肿瘤药物喜树碱)的耐受性呈现正相关;并且发现MEPE/OF45通过增强G2期检验点应答而增强肿瘤细胞对DNA损伤诱导剂的耐受性,进而提出人MEPE/OF45可能是一个肿瘤放疗、化疗的新靶点。
然而,DNA损伤应答相关信号通路错综复杂。MEPE/OF45通过与CHK1相互作用而调节细胞检验点应答的机制是否是MEPE/OF45参与细胞DNA损伤应答的唯一机制?MEPE/OF45作为细胞外基质蛋白,其功能如何与影响细胞DNA损伤应答的功能建立起联系?很多问题有待解决。
因此,为了进一步研究MEPE/OF45直接或间接调节的信号分子,探索MEPE/OF45增强细胞对DNA损伤诱导剂耐受性的分子机制,我们首先用基因表达谱芯片分析不同MEPE/OF45表达水平的细胞在DNA损伤诱导剂处理前后转录水平上基因表达的差异,结果获得上千条差异表达的基因信息。根据基因表达差异明显、功能与DNA损伤应答相关、研究进展较为深入等原则,选择29个候选基因进行半定量RT-PCR (Semi-Quantitative RT-PCR)验证,结果24个基因与芯片结果一致(79.2%)。为了排除细胞系的特异性,在另外2对MEPE/OF45不同表达水平的细胞系(MEPE/OF45高表达的A1-5细胞和MEPE/OF45低表达的B4细胞,稳定转染pREP10空载体的A1-5细胞和稳定转染反义MEPE/OF45的A1-5细胞)中验证差异基因18个,其中16个与芯片结果一致(89%)。
为了筛选DNA损伤应答相关基因,用半定量RT-PCR方法检测不同DNA损伤敏感性细胞中上述基因在DNA损伤诱导剂处理后转录水平的动力学表达情况,发现Serpinb2、Tgfβ2等基因转录水平受到DNA损伤诱导剂的影响。蛋白水平予以验证,发现SERPINB2是受细胞DNA损伤诱导剂诱导的基因。构建SERPINB2稳定表达细胞系,MTT比色实验发现SERPINB2能够提高细胞对DNA损伤诱导剂的耐受性。
芯片数据功能富集分析提示我们:DNA损伤诱导剂处理后,无论MEPE/OF45高表达还是低表达的细胞系,均激活了凋亡通路;且MEPE/OF45最相关的功能是负调控凋亡。为了获知MEPE/OF45是否真正影响细胞凋亡,我们分别检测了3对不同MEPE/OF45表达水平的细胞系(A1-5细胞和B4细胞、稳定转染MEPE/OF45的B4细胞和稳定转染pREP10空载体的B4细胞、稳定转染pREP10空载体的A1-5细胞和稳定转染反义MEPE/OF45的A1-5细胞)的凋亡敏感性,发现MEPE/OF45表达水平与细胞抗凋亡能力直接相关:过表达MEPE/OF45提高细胞抗凋亡能力;敲低MEPE/OF45的表达,细胞凋亡敏感性增加。所以我们得出与芯片结果一致的结论:MEPE/OF45能够抑制细胞凋亡。
进一步研究检测了细胞凋亡内源性途径和外源性途径的相关因子,包括死亡受体途径的Caspase 8与线粒体途径的Caspase 9。发现DNA损伤诱导剂引发的细胞凋亡过程中,Caspase 9被激活而Caspase 8没有被激活。说明MEPE/OF45影响的由DNA损伤诱导剂引发的细胞凋亡途径与线粒体凋亡通路相关。
那么MEPE/OF45影响细胞凋亡敏感性机制是怎样的呢?
我们前期工作证实MEPE/OF45通过结合CHK1而抑制后者降解。文献报道,DNA损伤发生后,CHK1能够磷酸化RB蛋白S612,促进其与转录因子E2F-1结合,进而抑制凋亡。于是,为了检测MEPE/OF45抗凋亡能力是否与其结合并稳定CHK1的功能相关,我们检测了稳定表达突变体MEPE/OF45(突变体MEPE/OF45与CHK1相互作用的能力较野生型MEPE/OF45显著下降)的B4细胞、稳定表达CHK1的B4细胞、稳定表达野生型MEPE/OF45的B4细胞以及稳定转染pREP10空载体的B4细胞的凋亡敏感性,发现稳定表达野生型MEPE/OF45的B4细胞、稳定表达CHK1的B4细胞表现出凋亡耐受性,而稳定表达突变体MEPE/OF45的B4细胞和稳定转染空载体的B4细胞均为凋亡敏感性细胞。也就是说,MEPE/OF45影响细胞凋亡依赖其与CHK1的相互作用。
此外,我们还注意到文献报道SERPINB2能够抑制RB蛋白降解,进而影响细胞凋亡。我们用半定量RT-PCR与免疫印迹方法都检测到MEPE/OF45高表达的同时会伴随SERPINB2在转录水平和蛋白水平的高表达。过表达MEPE/OF45的B4细胞,其SERPINB2、RB蛋白表达均上调。并且,过表达SERPINB2蛋白能够提高细胞抗凋亡能力。因此,MEPE/OF45高表达导致SERPINB2高表达,进而维持较高的RB水平,有可能是MEPE/OF45影响细胞凋亡敏感性的又一途径。
综上所述,我们的研究发现SERPINB2参与了DNA损伤应答;发现MEPE/OF45增强细胞抗凋亡能力,并且揭示MEPE/OF45影响DNA损伤诱导剂导致的细胞凋亡与线粒体凋亡途径相关;发现MEPE/OF45影响细胞凋亡依赖其与CHK1蛋白的相互作用,并与其上调SERPINB2蛋白和RB蛋白相关。
我们前期研究的结果和本研究结果提示:MEPE/OF45能够在调节细胞周期和抑制细胞凋亡两个不同层次上抑制DNA损伤诱导剂对细胞的杀伤作用。这不仅有助于加深对细胞DNA损伤应答机制的认识,还可能为今后放射治疗的靶分子研究提供有意义的线索。
Since MEPE/OF45 (Matrix Extracellular Phospho-glycoprotein/ Osteoblast/ Osteocyte Factor 45) was first cloned in 2000, however, its role as one member of SIBLING (Small Integrin-Binding Ligand N-linked Glycoprotein) family had been limited to regulation of bone metabolism and phosphate homeostasis. Our previous research has shown a new function of MEPE/OF45. That is, MEPE/OF45 is involved in cellular DNA damage response and affects cellular resistance to DNA damage inducers including ionising radiation (IR) and camptothecin (CPT) through its interaction with CHK1 (Checkpoint kinase 1) which reducing CHK1 interaction with E3 ligase and protecting CHK1 from the ubiquitin-mediated degradation. Wang’s group found hMEPE/OF45 (human MEPE/OF45) was generally expressed in tumour cell lines derived from almost all human tissues and expression level of hMEPE/OF45 correlated to the resistance of tumour cells to DNA damage inducers. hMEPE/OF45 increased the G2 checkpoint response and increased resistance of tumour cells to DNA damage inducers treatment. They proposed hMEPE/OF45 as a new target for sensitizing tumour cells to radiotherapy or chemotherapy.
However, is MEPE/OF45 regulating cellular checkpoint response through interacting with CHK1 the only mechanism by which MEPE/OF45 is involved in DNA damage response? What roles of MEPE/OF45 as a extracellular matrix protein are linked to its function affecting cellular DNA damage response?Many questions remain unsettled.
To further research signaling molecules affected directly or indirectly by MEPE/OF45 and uncover the potential molecular mechanisms through which MEPE/OF45 increasing cellular resistance to DNA damage inducers, gene microarray experiments were performed to analyze the differentially expressed genes between cells MEPE/OF45 highly expressed and ones MEPE/OF45 poorly expressed and between cells treated by DNA damage inducers and ones untreated by DNA damage inducers. Thousands of differentially expressed genes were found. To provide independent confirmation of microarray data, semi-quantitative PCR was performed on a selection of genes which were expressed significantly differentially, related to DNA damage response and researched generally. 24 genes among 29 genes show consistency between RT-PCR and microarray. To avoid specificity of cell lines, semi-quantitative PCR was performed in another two couples of cells (A1-5 highly expressing MEPE/OF45 and B4 poorly expressing MEPE/OF45, A1-5 transfected with pREP10 vector and A1-5 stably expressing antisense MEPE/OF45). 16 genes out of 18 showed consistent results.
To screen genes involved in DNA damage response, semi-quantitative PCR was performed to detect kinetic mRNA expression of candidate genes at different time points post-irradiation in different cells sensitive or resistant to IR. The mRNA expressions of Serpinb2 and Tgfβ2 were affected by IR exposure. The kinetic expressions of protein products were detected and SERPINB2 were identified to be induced by IR. Cell line stably expressing SERPINB2 was constructed and MTT assay showed that SERPINB2 increased cellular resistance to DNA damage inducers.
Microarray data analysis hinted that cell lines highly or poorly expressing MEPE/OF45 were induced apoptosis after DNA damage inducer treatment and the most possible function of MEPE/OF45 is inhibiting apoptosis. To identify whether MEPE/OF45 was involved in apoptosis response, we detected 3 couples of cells with different level of MEPE/OF45. We found that the level of MEPE/OF45 is correlated to cellular resistance to apoptosis. Over-expressing MEPE/OF45 increased the apoptosis resistance of cells while knocking down the expression of MEPE/OF45 made cells sensitive to apoptosis. Accordingly, we concluded that MEPE/OF45 made cells more resistant to apoptosis, which is coherent with the microarray assay.
Further study detected if Caspase 8 in extrinsic apoptosis pathway and/or Caspase 9 in intrinsic apoptosis pathway were/was activated after DNA damage inducer treatment. We found that only Caspase 9 was cleaved. Thus it is intrinsic apoptosis pathway by which MEPE/OF45 affected apoptosis induced by DNA damage inducer.
But what are the mechanisms underlying the anti-apoptosis roles of MEPE/OF45?
We previously showed that MEPE/OF45 stabilized CHK1 by its interaction with CHK1. It had been also reported CHK1 phosphorylated RB at S612 after DNA damage to promote RB binding to transcriptional factor E2F-1 which inhibited apoptosis. Then we detected the apoptotic sensitivity of couples of cells and found that cell line stably expressing MEPE/OF45 and cell line stably expressing CHK1 showed resistance to apoptosis while cell line stably transfected with pREP10 vector and cell line stably expressing mutant MEPE/OF45 (the interaction between mutant MEPE/OF45 and CHK1 is significant impaired compared to the interaction between wild MEPE/OF45 and CHK1) were sensitive to apoptosis. Conclusively, the anti-apoptosis role of MEPE/OF45 was related to its interaction with CHK1.
We also noted that SERPINB2 had been reported to protect RB from degradation by binding to RB and influence apoptosis. We found cells highly expressing MEPE/OF45 would highly express SERPINB2 simultaneously at transcriptional level and translation-level. Over-expressing MEPE/OF45 gave rise to upregulation of SERPINB2 and RB. Furthermore, highly expressing SERPINB2 protected cells from apoptosis. Therefore MEPE/OF45 promoting the expression of SERPINB2 which stabilizes RB may be another mechanism responsible for the anti-apoptosis role of MEPE/OF45.
Taken together, this study identified Serpinb2 as a gene related to DNA damage response, demonstrated that MEPE/OF45 increased cellular resistance to apoptosis induced by CPT through intrinsic apoptosis pathway and revealed that MEPE/OF45 inhibited apoptosis depending on its interaction with CHK1 and being related to it upregulating the level of SERPINB2 and RB.
Our study together with previous research suggested that MEPE/OF45 could protect cells from being killed by DNA damage inducers at different level including regulating cell cycles and inhibiting apoptosis. Our data will not only increase our knowledge on DNA damage response but also give a clue to future research concerned on targets of radiotherapy.
然而,DNA损伤应答相关信号通路错综复杂。MEPE/OF45通过与CHK1相互作用而调节细胞检验点应答的机制是否是MEPE/OF45参与细胞DNA损伤应答的唯一机制?MEPE/OF45作为细胞外基质蛋白,其功能如何与影响细胞DNA损伤应答的功能建立起联系?很多问题有待解决。
因此,为了进一步研究MEPE/OF45直接或间接调节的信号分子,探索MEPE/OF45增强细胞对DNA损伤诱导剂耐受性的分子机制,我们首先用基因表达谱芯片分析不同MEPE/OF45表达水平的细胞在DNA损伤诱导剂处理前后转录水平上基因表达的差异,结果获得上千条差异表达的基因信息。根据基因表达差异明显、功能与DNA损伤应答相关、研究进展较为深入等原则,选择29个候选基因进行半定量RT-PCR (Semi-Quantitative RT-PCR)验证,结果24个基因与芯片结果一致(79.2%)。为了排除细胞系的特异性,在另外2对MEPE/OF45不同表达水平的细胞系(MEPE/OF45高表达的A1-5细胞和MEPE/OF45低表达的B4细胞,稳定转染pREP10空载体的A1-5细胞和稳定转染反义MEPE/OF45的A1-5细胞)中验证差异基因18个,其中16个与芯片结果一致(89%)。
为了筛选DNA损伤应答相关基因,用半定量RT-PCR方法检测不同DNA损伤敏感性细胞中上述基因在DNA损伤诱导剂处理后转录水平的动力学表达情况,发现Serpinb2、Tgfβ2等基因转录水平受到DNA损伤诱导剂的影响。蛋白水平予以验证,发现SERPINB2是受细胞DNA损伤诱导剂诱导的基因。构建SERPINB2稳定表达细胞系,MTT比色实验发现SERPINB2能够提高细胞对DNA损伤诱导剂的耐受性。
芯片数据功能富集分析提示我们:DNA损伤诱导剂处理后,无论MEPE/OF45高表达还是低表达的细胞系,均激活了凋亡通路;且MEPE/OF45最相关的功能是负调控凋亡。为了获知MEPE/OF45是否真正影响细胞凋亡,我们分别检测了3对不同MEPE/OF45表达水平的细胞系(A1-5细胞和B4细胞、稳定转染MEPE/OF45的B4细胞和稳定转染pREP10空载体的B4细胞、稳定转染pREP10空载体的A1-5细胞和稳定转染反义MEPE/OF45的A1-5细胞)的凋亡敏感性,发现MEPE/OF45表达水平与细胞抗凋亡能力直接相关:过表达MEPE/OF45提高细胞抗凋亡能力;敲低MEPE/OF45的表达,细胞凋亡敏感性增加。所以我们得出与芯片结果一致的结论:MEPE/OF45能够抑制细胞凋亡。
进一步研究检测了细胞凋亡内源性途径和外源性途径的相关因子,包括死亡受体途径的Caspase 8与线粒体途径的Caspase 9。发现DNA损伤诱导剂引发的细胞凋亡过程中,Caspase 9被激活而Caspase 8没有被激活。说明MEPE/OF45影响的由DNA损伤诱导剂引发的细胞凋亡途径与线粒体凋亡通路相关。
那么MEPE/OF45影响细胞凋亡敏感性机制是怎样的呢?
我们前期工作证实MEPE/OF45通过结合CHK1而抑制后者降解。文献报道,DNA损伤发生后,CHK1能够磷酸化RB蛋白S612,促进其与转录因子E2F-1结合,进而抑制凋亡。于是,为了检测MEPE/OF45抗凋亡能力是否与其结合并稳定CHK1的功能相关,我们检测了稳定表达突变体MEPE/OF45(突变体MEPE/OF45与CHK1相互作用的能力较野生型MEPE/OF45显著下降)的B4细胞、稳定表达CHK1的B4细胞、稳定表达野生型MEPE/OF45的B4细胞以及稳定转染pREP10空载体的B4细胞的凋亡敏感性,发现稳定表达野生型MEPE/OF45的B4细胞、稳定表达CHK1的B4细胞表现出凋亡耐受性,而稳定表达突变体MEPE/OF45的B4细胞和稳定转染空载体的B4细胞均为凋亡敏感性细胞。也就是说,MEPE/OF45影响细胞凋亡依赖其与CHK1的相互作用。
此外,我们还注意到文献报道SERPINB2能够抑制RB蛋白降解,进而影响细胞凋亡。我们用半定量RT-PCR与免疫印迹方法都检测到MEPE/OF45高表达的同时会伴随SERPINB2在转录水平和蛋白水平的高表达。过表达MEPE/OF45的B4细胞,其SERPINB2、RB蛋白表达均上调。并且,过表达SERPINB2蛋白能够提高细胞抗凋亡能力。因此,MEPE/OF45高表达导致SERPINB2高表达,进而维持较高的RB水平,有可能是MEPE/OF45影响细胞凋亡敏感性的又一途径。
综上所述,我们的研究发现SERPINB2参与了DNA损伤应答;发现MEPE/OF45增强细胞抗凋亡能力,并且揭示MEPE/OF45影响DNA损伤诱导剂导致的细胞凋亡与线粒体凋亡途径相关;发现MEPE/OF45影响细胞凋亡依赖其与CHK1蛋白的相互作用,并与其上调SERPINB2蛋白和RB蛋白相关。
我们前期研究的结果和本研究结果提示:MEPE/OF45能够在调节细胞周期和抑制细胞凋亡两个不同层次上抑制DNA损伤诱导剂对细胞的杀伤作用。这不仅有助于加深对细胞DNA损伤应答机制的认识,还可能为今后放射治疗的靶分子研究提供有意义的线索。
Since MEPE/OF45 (Matrix Extracellular Phospho-glycoprotein/ Osteoblast/ Osteocyte Factor 45) was first cloned in 2000, however, its role as one member of SIBLING (Small Integrin-Binding Ligand N-linked Glycoprotein) family had been limited to regulation of bone metabolism and phosphate homeostasis. Our previous research has shown a new function of MEPE/OF45. That is, MEPE/OF45 is involved in cellular DNA damage response and affects cellular resistance to DNA damage inducers including ionising radiation (IR) and camptothecin (CPT) through its interaction with CHK1 (Checkpoint kinase 1) which reducing CHK1 interaction with E3 ligase and protecting CHK1 from the ubiquitin-mediated degradation. Wang’s group found hMEPE/OF45 (human MEPE/OF45) was generally expressed in tumour cell lines derived from almost all human tissues and expression level of hMEPE/OF45 correlated to the resistance of tumour cells to DNA damage inducers. hMEPE/OF45 increased the G2 checkpoint response and increased resistance of tumour cells to DNA damage inducers treatment. They proposed hMEPE/OF45 as a new target for sensitizing tumour cells to radiotherapy or chemotherapy.
However, is MEPE/OF45 regulating cellular checkpoint response through interacting with CHK1 the only mechanism by which MEPE/OF45 is involved in DNA damage response? What roles of MEPE/OF45 as a extracellular matrix protein are linked to its function affecting cellular DNA damage response?Many questions remain unsettled.
To further research signaling molecules affected directly or indirectly by MEPE/OF45 and uncover the potential molecular mechanisms through which MEPE/OF45 increasing cellular resistance to DNA damage inducers, gene microarray experiments were performed to analyze the differentially expressed genes between cells MEPE/OF45 highly expressed and ones MEPE/OF45 poorly expressed and between cells treated by DNA damage inducers and ones untreated by DNA damage inducers. Thousands of differentially expressed genes were found. To provide independent confirmation of microarray data, semi-quantitative PCR was performed on a selection of genes which were expressed significantly differentially, related to DNA damage response and researched generally. 24 genes among 29 genes show consistency between RT-PCR and microarray. To avoid specificity of cell lines, semi-quantitative PCR was performed in another two couples of cells (A1-5 highly expressing MEPE/OF45 and B4 poorly expressing MEPE/OF45, A1-5 transfected with pREP10 vector and A1-5 stably expressing antisense MEPE/OF45). 16 genes out of 18 showed consistent results.
To screen genes involved in DNA damage response, semi-quantitative PCR was performed to detect kinetic mRNA expression of candidate genes at different time points post-irradiation in different cells sensitive or resistant to IR. The mRNA expressions of Serpinb2 and Tgfβ2 were affected by IR exposure. The kinetic expressions of protein products were detected and SERPINB2 were identified to be induced by IR. Cell line stably expressing SERPINB2 was constructed and MTT assay showed that SERPINB2 increased cellular resistance to DNA damage inducers.
Microarray data analysis hinted that cell lines highly or poorly expressing MEPE/OF45 were induced apoptosis after DNA damage inducer treatment and the most possible function of MEPE/OF45 is inhibiting apoptosis. To identify whether MEPE/OF45 was involved in apoptosis response, we detected 3 couples of cells with different level of MEPE/OF45. We found that the level of MEPE/OF45 is correlated to cellular resistance to apoptosis. Over-expressing MEPE/OF45 increased the apoptosis resistance of cells while knocking down the expression of MEPE/OF45 made cells sensitive to apoptosis. Accordingly, we concluded that MEPE/OF45 made cells more resistant to apoptosis, which is coherent with the microarray assay.
Further study detected if Caspase 8 in extrinsic apoptosis pathway and/or Caspase 9 in intrinsic apoptosis pathway were/was activated after DNA damage inducer treatment. We found that only Caspase 9 was cleaved. Thus it is intrinsic apoptosis pathway by which MEPE/OF45 affected apoptosis induced by DNA damage inducer.
But what are the mechanisms underlying the anti-apoptosis roles of MEPE/OF45?
We previously showed that MEPE/OF45 stabilized CHK1 by its interaction with CHK1. It had been also reported CHK1 phosphorylated RB at S612 after DNA damage to promote RB binding to transcriptional factor E2F-1 which inhibited apoptosis. Then we detected the apoptotic sensitivity of couples of cells and found that cell line stably expressing MEPE/OF45 and cell line stably expressing CHK1 showed resistance to apoptosis while cell line stably transfected with pREP10 vector and cell line stably expressing mutant MEPE/OF45 (the interaction between mutant MEPE/OF45 and CHK1 is significant impaired compared to the interaction between wild MEPE/OF45 and CHK1) were sensitive to apoptosis. Conclusively, the anti-apoptosis role of MEPE/OF45 was related to its interaction with CHK1.
We also noted that SERPINB2 had been reported to protect RB from degradation by binding to RB and influence apoptosis. We found cells highly expressing MEPE/OF45 would highly express SERPINB2 simultaneously at transcriptional level and translation-level. Over-expressing MEPE/OF45 gave rise to upregulation of SERPINB2 and RB. Furthermore, highly expressing SERPINB2 protected cells from apoptosis. Therefore MEPE/OF45 promoting the expression of SERPINB2 which stabilizes RB may be another mechanism responsible for the anti-apoptosis role of MEPE/OF45.
Taken together, this study identified Serpinb2 as a gene related to DNA damage response, demonstrated that MEPE/OF45 increased cellular resistance to apoptosis induced by CPT through intrinsic apoptosis pathway and revealed that MEPE/OF45 inhibited apoptosis depending on its interaction with CHK1 and being related to it upregulating the level of SERPINB2 and RB.
Our study together with previous research suggested that MEPE/OF45 could protect cells from being killed by DNA damage inducers at different level including regulating cell cycles and inhibiting apoptosis. Our data will not only increase our knowledge on DNA damage response but also give a clue to future research concerned on targets of radiotherapy.
引文
[1] Rowe PSN, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics. 2000, 67(1):54-68.
[2] Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem. 2000, 275(46):36172-80.
[3] MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res, 2002, 43(2-3): 320-330.
[4] Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics. 2001, 74(3):342-51.
[5] Rowe PSN, Kumagai Y, Gutierrez G, et al. MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 2004, 34(2):303–19.
[6] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 83(3):R1-9.
[7] Rowe PSN, Garrett IR, Schwarz PM, et al. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone. 2005, 36(1):33-46.
[8] Addison WN, Nakano Y, Loisel T, et al. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res. 2008, 23(10):1638-49.
[9] Sprowson AP, McCaskie AW, Birch MA. ASARM-truncated MEPE and AC-100 enhance osteogenesis by promoting osteoprogenitor adhesion. J Orthop Res. 2008, 26(9):1256-62.
[10] Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res. 2004, 19(3):455-62.
[11] Liu H, Li W, Gao C, et al. Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res. 2004, 83(6):496-9.
[12] Céline G, Tchilalo B, Dominique S, et al. Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets. Cells Tissues Organs. 2009, 189(1-4):219-223.
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[1] Rowe PS, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia.Genomics. 2000, 67(1):54-68.
[2] Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem. 2000, 275(46):36172-80.
[3] MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res, 2002, 43(2-3): 320-330.
[4] Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics. 2001, 74(3):342-51.
[5] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 83(3):R1-9.
[6] Rowe PS, Garrett IR, Schwarz PM, et al. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model forimpaired mineralization in X-linked rickets (HYP).Bone. 2005, 36(1):33-46.
[7] Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res. 2004, 19(3):455-62.
[8] Liu H, Li W, Gao C, et al. Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res. 2004, 83(6):496-9.
[9] Lu C, Huang S, Miclau T, et al. Mepe is expressed during skeletal development and regeneration. Histochem Cell Biol. 2004, 121(6):493-499.
[10] Siggelkow H, Schmidt E, Hennies B, et al. Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts. Bone. 2004, 35(2):570-6.
[11] Harris SE, Gluhak HJ, Harris MA, et al. DMP1 and MEPE expression are elevated in osteocytes after mechanical loading in vivo: theoretical role in controlling mineral quality in the perilacunar matrix. J Musculoskelet Neuronal Interact. 2007, 7(4):313-5.
[12] David V, Martin A, Hedge AM, et al. Matrix extracellular phosphoglycoprotein (MEPE) is a new bone renal hormone and vascularization modulator. Endocrinology. 2009, 150(9):4012-23.
[13] Liu S, Guo R, Simpson LG, et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003, 278(39):37419-26.
[14] Gowen LC, Petersen DN, Mansolf AL, et al. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass.J Biol Chem. 2003, 278(3):1998-2007.
[15] Liu S, Brown TA, Zhou J, et al. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol. 2005, 16(6): 1645-53.
[16] Nagel DE, Khosla S, Sanyal A, et al. A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase-2 to exert potent anabolic effects on normal human marrow osteoblast precursors. J Cell Biochem. 2004, 93(6):1107-14.
[17] Six N, Septier D, Chaussain-Miller C, Blacher R, et al. Dentonin, a MEPE fragment, initiates pulp-healing response to injury. J Dent Res. 2007, 86(8):780-5.
[18] Sprowson AP, McCaskie AW, Birch MA. ASARM-truncated MEPE and AC-100 enhance osteogenesis by promoting osteoprogenitor adhesion. J Orthop Res. 2008, 26(9):1256-62.
[19] Addison WN, Nakano Y, Loisel T, et al. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res. 2008, 23(10):1638-49.
[20] Céline G, Tchilalo B, Dominique S, et al. Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets. Cells Tissues Organs. 2009, 189(1-4):219-223.
[21] Boskey AL, Chiang P, Fermanis A, et al. MEPE's diverse effects on mineralization. Calcif Tissue Int. 2010, 86(1):42-6.
[22] Pawel RK, Fayez K Ghishan. Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis. Laboratory Investigation. 2009, 89(1):7-14.
[23] Guo R, Rowe PS, Liu S, et al. Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun. 2002, 297(1):38-45.
[24] Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003, 285(1):E1-9.
[25] Bacic D, Wagner CA, Hernando N, et al. Novel aspects in regulated express of the renal type IIa Na/Pi-cotransporter. Kidney Int Suppl. 2004, 66(91):S5-S12.
[26] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 183(3):R1-9.
[27] Jain A, Fedarko NS, Collins MT, et al. Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. J Clin Endocrinol Metab. 2004, 89 (8): 4158-61.
[28] Martinez J, Georgoff I, Martinez J, et al. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Genes & Development, 1991, 5(2): 151-159.
[29]胡宝成, Iliakis G,王亚.转化的大鼠胚胎成纤维细胞系与p53val135功能关系的研究.生物技术通讯. 2002, 13(1):18-22.
[30] Cho HN, Lee SJ, Park SH, et al. Overexpression of hest-shock protein 25 augments radiation-induce cell-cycle arrest in murine L929 cells. Int J Radiat Biol, 2001, 77(2): 225-233.
[31] Baust H, Schoke A, Brey A, et al. Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms. Oncogene. 2003, 22(54):8786-96.
[32] Hu B, Zhou XY, Wang X, et al. The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway. J Biol Chem. 2001, 276(21): 17693-17698.
[33]胡宝成,王翔, Iliakis G.转化的大鼠胚胎成纤维细胞系差异表达基因的筛选研究.生物技术通讯. 2002, 13(2):118-125.
[34] Liu S, Wang H, Wang X, et al. MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1. Nucleic Acids Res. 2009, 37(22):7447-54.
[35]胡宝成,薛恒钢,刘爽.一种新的抗辐射性相关蛋白AA12和CHK1相互作用的研究.军事医学科学院院刊. 2003, 27(5):345-348.
[36] Zhang YW, Otterness DM, Chiang GG, et al. Genotoxic stress targets human Chk1 for degradation by the ubiquitin-proteasome pathway. Mol Cell. 2005, 19(5): 607–618.
[37] Zhang P, Wang H, Rowe PS, et al. MEPE/OF45 as a new target for sensitizing human tumour cells to DNA damage inducers. Br J Cancer. 2010, 102(5):862-6.
[38] Cho YD, Yoon WJ, Woo KM, et al. Molecular regulation of matrix extracellular phosphoglycoprotein expression by bone morphogenetic protein-2. J Biol Chem. 2009, 284(37):25230-40.
[1]Rowe PSN, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia[J]. Genomics, 2000, 67(1): 54-68.
[2]Hara S, Iida R, Yoshida H, et al. The role of phosphatonin in phosphate metabolism[J]. Clin Calcium, 2005, 15(7): 124-130.
[3]Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo[J]. J Bone Miner Res, 2004, 19(3): 455-462.
[4]Rowe PSN, Kumagai Y, Gutierrez G, et al. MEPE has the properties of an osteoblastic phosphatonin and minhibin[J]. Bone, 2004, 34(2): 303-319.
[5]Berndt TJ, Schiavi S, Kumar R, et al. "Phosphatonins" and the regulation of phosphorus homeostasis[J]. Am J Physiol Renal Physiol, 2005, 289(6): 1170-1182
[6]Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes[J]. J Biol Chem, 2000, 275(46): 36172-36180.
[7]Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone[J]. Genomics, 2001, 74(3): 342-351.
[8]MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21[J]. ConnectTissue Res, 2002, 43(2-3): 320-330.
[9]Liu S, Wang H, Wang X, et al. MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1[J]. Nucleic Acids Res, 2009, 37(22): 7447-7454.
[10]胡宝成,Iliakis G,王亚.转化的大鼠胚胎成纤维细胞系与p53val135功能关系的研究[J].生物技术通讯, 2002, 13(1): 18-22.
[11]胡宝成,王翔,Iliakis G,等.转化的大鼠胚胎成纤维细胞系差异表达基因的筛选研究[J].生物技术通讯, 2002, 13(2): 118-125.
[12]胡宝成,薛恒钢,刘爽,等.一种新的抗辐射性相关蛋白AA12和CHK1相互作用的研究[J].军事医学科学院院刊, 2003, 27(5): 345-348.
[13]Jiang K, Pereira E, Maxfield M. Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345[J]. J Biol Chem, 2003, 278(27): 25207-25217.文章发表于军事医学科学院院刊34(2):123-126.
[2] Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem. 2000, 275(46):36172-80.
[3] MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res, 2002, 43(2-3): 320-330.
[4] Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics. 2001, 74(3):342-51.
[5] Rowe PSN, Kumagai Y, Gutierrez G, et al. MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 2004, 34(2):303–19.
[6] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 83(3):R1-9.
[7] Rowe PSN, Garrett IR, Schwarz PM, et al. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone. 2005, 36(1):33-46.
[8] Addison WN, Nakano Y, Loisel T, et al. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res. 2008, 23(10):1638-49.
[9] Sprowson AP, McCaskie AW, Birch MA. ASARM-truncated MEPE and AC-100 enhance osteogenesis by promoting osteoprogenitor adhesion. J Orthop Res. 2008, 26(9):1256-62.
[10] Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res. 2004, 19(3):455-62.
[11] Liu H, Li W, Gao C, et al. Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res. 2004, 83(6):496-9.
[12] Céline G, Tchilalo B, Dominique S, et al. Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets. Cells Tissues Organs. 2009, 189(1-4):219-223.
[13] Lu C, Huang S, Miclau T, et al. Mepe is expressed during skeletal development and regeneration. Histochem Cell Biol. 2004, 121(6):493-499.
[14] Siggelkow H, Schmidt E, Hennies B, et al. Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts. Bone. 2004, 35(2):570-6.
[15] Harris SE, Gluhak HJ, Harris MA, et al. DMP1 and MEPE expression are elevated in osteocytes after mechanical loading in vivo: theoretical role in controlling mineral quality in the perilacunar matrix. J Musculoskelet Neuronal Interact. 2007, 7(4):313-5.
[16] David V, Martin A, Hedge AM, et al. Matrix extracellular phosphoglycoprotein (MEPE) is a new bone renal hormone and vascularization modulator. Endocrinology. 2009, 150(9):4012-23.
[17] Liu S, Guo R, Simpson LG, et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003, 278(39):37419-26.
[18] Gowen LC, Petersen DN, Mansolf AL, et al. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass.J Biol Chem. 2003, 278(3):1998-2007.
[19] Liu S, Brown TA, Zhou J, et al. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol. 2005, 16(6): 1645-53.
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[1] Rowe PS, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia.Genomics. 2000, 67(1):54-68.
[2] Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem. 2000, 275(46):36172-80.
[3] MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res, 2002, 43(2-3): 320-330.
[4] Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics. 2001, 74(3):342-51.
[5] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 83(3):R1-9.
[6] Rowe PS, Garrett IR, Schwarz PM, et al. Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model forimpaired mineralization in X-linked rickets (HYP).Bone. 2005, 36(1):33-46.
[7] Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res. 2004, 19(3):455-62.
[8] Liu H, Li W, Gao C, et al. Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res. 2004, 83(6):496-9.
[9] Lu C, Huang S, Miclau T, et al. Mepe is expressed during skeletal development and regeneration. Histochem Cell Biol. 2004, 121(6):493-499.
[10] Siggelkow H, Schmidt E, Hennies B, et al. Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts. Bone. 2004, 35(2):570-6.
[11] Harris SE, Gluhak HJ, Harris MA, et al. DMP1 and MEPE expression are elevated in osteocytes after mechanical loading in vivo: theoretical role in controlling mineral quality in the perilacunar matrix. J Musculoskelet Neuronal Interact. 2007, 7(4):313-5.
[12] David V, Martin A, Hedge AM, et al. Matrix extracellular phosphoglycoprotein (MEPE) is a new bone renal hormone and vascularization modulator. Endocrinology. 2009, 150(9):4012-23.
[13] Liu S, Guo R, Simpson LG, et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003, 278(39):37419-26.
[14] Gowen LC, Petersen DN, Mansolf AL, et al. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass.J Biol Chem. 2003, 278(3):1998-2007.
[15] Liu S, Brown TA, Zhou J, et al. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. J Am Soc Nephrol. 2005, 16(6): 1645-53.
[16] Nagel DE, Khosla S, Sanyal A, et al. A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase-2 to exert potent anabolic effects on normal human marrow osteoblast precursors. J Cell Biochem. 2004, 93(6):1107-14.
[17] Six N, Septier D, Chaussain-Miller C, Blacher R, et al. Dentonin, a MEPE fragment, initiates pulp-healing response to injury. J Dent Res. 2007, 86(8):780-5.
[18] Sprowson AP, McCaskie AW, Birch MA. ASARM-truncated MEPE and AC-100 enhance osteogenesis by promoting osteoprogenitor adhesion. J Orthop Res. 2008, 26(9):1256-62.
[19] Addison WN, Nakano Y, Loisel T, et al. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res. 2008, 23(10):1638-49.
[20] Céline G, Tchilalo B, Dominique S, et al. Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets. Cells Tissues Organs. 2009, 189(1-4):219-223.
[21] Boskey AL, Chiang P, Fermanis A, et al. MEPE's diverse effects on mineralization. Calcif Tissue Int. 2010, 86(1):42-6.
[22] Pawel RK, Fayez K Ghishan. Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis. Laboratory Investigation. 2009, 89(1):7-14.
[23] Guo R, Rowe PS, Liu S, et al. Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun. 2002, 297(1):38-45.
[24] Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003, 285(1):E1-9.
[25] Bacic D, Wagner CA, Hernando N, et al. Novel aspects in regulated express of the renal type IIa Na/Pi-cotransporter. Kidney Int Suppl. 2004, 66(91):S5-S12.
[26] Bresler D, Bruder J, Mohnike K, et al. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004, 183(3):R1-9.
[27] Jain A, Fedarko NS, Collins MT, et al. Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. J Clin Endocrinol Metab. 2004, 89 (8): 4158-61.
[28] Martinez J, Georgoff I, Martinez J, et al. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Genes & Development, 1991, 5(2): 151-159.
[29]胡宝成, Iliakis G,王亚.转化的大鼠胚胎成纤维细胞系与p53val135功能关系的研究.生物技术通讯. 2002, 13(1):18-22.
[30] Cho HN, Lee SJ, Park SH, et al. Overexpression of hest-shock protein 25 augments radiation-induce cell-cycle arrest in murine L929 cells. Int J Radiat Biol, 2001, 77(2): 225-233.
[31] Baust H, Schoke A, Brey A, et al. Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms. Oncogene. 2003, 22(54):8786-96.
[32] Hu B, Zhou XY, Wang X, et al. The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway. J Biol Chem. 2001, 276(21): 17693-17698.
[33]胡宝成,王翔, Iliakis G.转化的大鼠胚胎成纤维细胞系差异表达基因的筛选研究.生物技术通讯. 2002, 13(2):118-125.
[34] Liu S, Wang H, Wang X, et al. MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1. Nucleic Acids Res. 2009, 37(22):7447-54.
[35]胡宝成,薛恒钢,刘爽.一种新的抗辐射性相关蛋白AA12和CHK1相互作用的研究.军事医学科学院院刊. 2003, 27(5):345-348.
[36] Zhang YW, Otterness DM, Chiang GG, et al. Genotoxic stress targets human Chk1 for degradation by the ubiquitin-proteasome pathway. Mol Cell. 2005, 19(5): 607–618.
[37] Zhang P, Wang H, Rowe PS, et al. MEPE/OF45 as a new target for sensitizing human tumour cells to DNA damage inducers. Br J Cancer. 2010, 102(5):862-6.
[38] Cho YD, Yoon WJ, Woo KM, et al. Molecular regulation of matrix extracellular phosphoglycoprotein expression by bone morphogenetic protein-2. J Biol Chem. 2009, 284(37):25230-40.
[1]Rowe PSN, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia[J]. Genomics, 2000, 67(1): 54-68.
[2]Hara S, Iida R, Yoshida H, et al. The role of phosphatonin in phosphate metabolism[J]. Clin Calcium, 2005, 15(7): 124-130.
[3]Hayashibara T, Hiraga T, Yi B, et al. A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo[J]. J Bone Miner Res, 2004, 19(3): 455-462.
[4]Rowe PSN, Kumagai Y, Gutierrez G, et al. MEPE has the properties of an osteoblastic phosphatonin and minhibin[J]. Bone, 2004, 34(2): 303-319.
[5]Berndt TJ, Schiavi S, Kumar R, et al. "Phosphatonins" and the regulation of phosphorus homeostasis[J]. Am J Physiol Renal Physiol, 2005, 289(6): 1170-1182
[6]Petersen DN, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes[J]. J Biol Chem, 2000, 275(46): 36172-36180.
[7]Argiro L, Desbarats M, Glorieux FH, et al. Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone[J]. Genomics, 2001, 74(3): 342-351.
[8]MacDougall M, Simmons D, Gu TT, et al. OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21[J]. ConnectTissue Res, 2002, 43(2-3): 320-330.
[9]Liu S, Wang H, Wang X, et al. MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1[J]. Nucleic Acids Res, 2009, 37(22): 7447-7454.
[10]胡宝成,Iliakis G,王亚.转化的大鼠胚胎成纤维细胞系与p53val135功能关系的研究[J].生物技术通讯, 2002, 13(1): 18-22.
[11]胡宝成,王翔,Iliakis G,等.转化的大鼠胚胎成纤维细胞系差异表达基因的筛选研究[J].生物技术通讯, 2002, 13(2): 118-125.
[12]胡宝成,薛恒钢,刘爽,等.一种新的抗辐射性相关蛋白AA12和CHK1相互作用的研究[J].军事医学科学院院刊, 2003, 27(5): 345-348.
[13]Jiang K, Pereira E, Maxfield M. Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345[J]. J Biol Chem, 2003, 278(27): 25207-25217.文章发表于军事医学科学院院刊34(2):123-126.
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